Oxidative stress is a key mechanism in the pathogenesis of a multitude of diseases and disorders. Indeed, hyperoxia, hypoxia, ischemia, cytokines, hyperhycemia, and other pathological factors have each been shown to induce endothelial production of toxic oxidants and the expression of cell adhesion molecules that are then used by leukocytes to bind to and migrate through endothelial cells. Moreover, the oxidants produced by endothelial cells and released by leukocytes damage the endothelium, thereby inducing a vicious cycle of inflammation, edema, thrombosis, and vascular dysfunctions, all of which further propagate primary disease conditions.
More recently, studies have also linked biodegradable biomaterial-induced inflammatory responses to cellular oxidative stress, where inflammatory cells such as macrophages release a plethora of inflammatory cytokines and reactive oxygen and nitrogen species (ROS and RNS) [4, 39, 44]. In the case of biodegradable polymers, this biomaterial-induced inflammation and toxicity is often a result of local accumulation of polymer degradation products. As such, the conjugation of antioxidant molecules to polymers has been proposed as one means by which biomaterial-induced inflammation and oxidative stress may be suppressed [18, 42, 44, 47, 50]. To date, however, these conjugated antioxidant polymer systems have only been capable of incorporating a low percent content of antioxidants as compared to the bulk material and have only been capable of incorporating a limited range of antioxidants. Other systems have produced polymers with one-hundred percent antioxidant content, but those systems have exhibited limited control over degradation rates of the polymers and have also shown to only be a capable of being extended to a few other antioxidants. For example, a poly(trolox ester) polymer or, in other words, a polymer of trolox (the water-soluble analogue of tocopherol) has been developed that has one-hundred percent antioxidant content, but has been shown to undergo enzymatic degradation and to be limited by its lack of hydrolytic degradation, leaving very little control over its degradation rate.
Accordingly, a polymeric biomaterial that provides enhanced control over the degradation rate of the biomaterial, but yet also is capable of incorporating a sufficient variety and/or amount of antioxidants in the polymer system would be both highly-desirable and beneficial for reducing oxidative stress.